抑郁症与血管内皮功能失调：内皮祖细胞和Notch信号通路的作用

Major depression is associated with an increased risk of coronary artery disease. Vascular endothelial dysfunction is thought to be a key event in the initiation and progression of coronary artery disease. Our previous study found that major depression can lead to vascular endothelial dysfunction. However, the mechanism underlying vascular endothelial dysfunction in the presence of major depression remains largely unknown. Endothelial progenitor cells (EPCs), which serve as the precursor of vascular endothelium, play an important role in maintain the integrality of vascular endothelial structure and function, and furthermore, several latest studies demonstrated that the fate and function of EPCs were mainly regulated by the Notch signaling pathway. Therefore, we hypothesize that: (1) vascular endothelial dysfunction during major depression can be accounted for by the impaired EPCs, (2) the impairment of EPCs due to major depression is mediated by the Notch signaling pathway. In order to test the hypotheses as described above, this project consists of two parts of scientific investigations. First, we will perform the following determinations in eligible patients with and without major depressive disorder: 1) brachial artery flow-mediated dilation (the most commonly used noninvasive assessment of vascular endothelial function), circulating endothelial microparticles and nitric oxide levels, 2) apoptosis, senescence and function in EPCs, 3) the expression of Notch receptors and their ligands in EPCs. The results of these studies aim to clarify the relationship between vascular endothelial dysfunction and impaired EPCs, and screen out the potential members of the Notch signaling pathway which are responsible for the impairment of EPCs during major depression. Second, we will measure the alterations of apoptosis, senescence and function in EPCs in eligible patients with and without major depression, after upregulating or downregulating the Notch signaling pathway which were screened out in the first part study using specific tool drugs, gene over-expression or knock-down. The results of these studies aim to identify the crucial player in the Notch signaling pathway which are involved in the impairment of EPCs during major depression. In conclusion, this project is intended to uncover the underlying mechanisms of and provide potential therapeutic targets for vascular endothelial dysfunction and elevated risk for the initiation and progression of coronary artery disease in individuals suffering from major depression.

血管内皮功能失调是引起冠心病发生的始动环节和加速冠心病发展的重要因素。我们前期发现抑郁症可引起血管内皮功能失调，但其机制仍未阐明。内皮祖细胞（EPCs）对维持血管内皮结构和功能的完整极其重要，其功能和命运主要受Notch信号通路调控。因此，我们推测抑郁症时血管内皮功能失调与EPCs和Notch信号通路异常有关。本项目入选抑郁症患者和非抑郁对照者，分别检测：1)血管内皮功能、2)EPCs凋亡、衰老和功能、3) EPCs中Notch受体和配体表达，明确抑郁症时血管内皮功能失调与EPCs受损的关系，并筛选出参与EPCs受损的Notch成员；然后运用药物、基因过表达或RNA干扰技术双向调节上述筛选出的Notch成员功能，观察EPCs凋亡、衰老和功能的变化，证实出在抑郁症引起EPCs受损中发挥关键作用的Notch成员；为抑郁症时血管内皮功能失调以及冠心病发生和发展风险增加提供机制解释和干预靶点。

通过一系列临床、细胞以及分子层面的研究，本项目发现：1）抑郁症患者血管内皮功能受损，主要表现为内皮依赖性血管扩张（反应性充血血流量以及血流介导的血管扩张）明显降低、血浆一氧化氮水平明显减低、血浆内皮微颗粒数明显增多。2）抑郁症患者外周血内皮祖细胞数量减少、内皮祖细胞凋亡和衰老增加以及内皮祖细胞的主要功能包括增殖、迁移、粘附以及血管新生能力下降。3）抑郁症患者内皮祖细胞Notch4的mRNA及蛋白表达均明显增加。这些结果提示，抑郁症患者血管内皮功能受损同内皮祖细胞数量较少及功能下降有关，具体分子机制可能由内皮祖细胞中Notch4信号通路异常介导。通过这一系列研究，阐明了抑郁症时血管内皮功能受损的机制，为其防治提供潜在靶点。